Bovy et al, U.S. Pat. No. 5,430,043 describe phenyl amidines of the formula: ##STR2## which are reported to be platelet aggregation inhibitors. However, no mention is made of inhibiting Factor Xa.
Himmelsbach et al, CA 2,105,934, address cyclic ureas of the formula: ##STR3## wherein, among the multitude of choices, X may be a carbonyl, Y may be an C.sub.2-4 alkylene, R.sub.a may be A--B--C-- and R.sub.b may be --D--E--F. Group F is selected from --CO.sub.2 R, phosphono, tetrazolyl, and R.sub.8 CO--O--CHR.sub.9 --O--CO--. The compounds described by the above formula are alleged to have aggregation inhibiting and/or fibrinogen binding properties. Factor Xa inhibiting is not discussed.
Lam et al, WO 94/19329, report cyclic carbonyls which may be cyclic ureas of the formula: ##STR4## wherein at least one of R.sup.4, R.sup.4a, R.sup.7, and R.sup.7a is other than hydrogen. Compounds of this sort are said to be useful as HIV protease inhibitors. N-(Amidinophenyl)cycloureas are not suggested as factor Xa inhibitors.
Currie et al, WO 96/36639, set forth amidine derivatives of the formula: ##STR5## wherein A may be a 6-membered cyclic urea, which may be useful as anti-platelet aggregation inhibitors. However, Y is nitrate, nitrite, or a nitric oxide donating group. The present compounds, in contrast, do not contain the nitric oxide donating groups of WO 96/36639.
Klinger et al, WO 94/21607, illustrate heterocyclic compounds of the formula: ##STR6## wherein, upon judicious selection of variables, Z.sup.1 may be a carbonyl, A may be NR.sup.1, R.sup.1 may be an amidino-substituted phenyl, and B and Z.sup.2 may each be CH.sub.2. However, the present compounds do not include the right-side chain shown above.
Mohan et al, WO 96/38421, describe N,N-di(arylmethyl)cyclic urea derivatives of the formula: ##STR7## wherein R.sup.7 and R.sup.8 may combine to form a benzene ring and the double bond shown may be absent, which may be useful as Factor Xa inhibitors. These compounds are preferably bis-amidino substituted. However, the presently claimed compounds are neither bis-benzyl nor bis-amidino substituted.
Chakravarty et al, WO 95/03044, discuss benzimidazoles substituted with phenoxyphenylacetic acid dervatives of the formula: ##STR8## wherein R.sup.12 may be a substituted aryl group. But, this reference does not consider amidino-phenyl groups. Furthermore, the present compounds do not contain the above variable Z, which is defined as a carbonyl, sulfonyl, or phosphoryl group.
Activated factor Xa, whose major practical role is the generation of thrombin by the limited proteolysis of prothrombin, holds a central position that links the intrinsic and extrinsic activation mechanisms in the final common pathway of blood coagulation. The generation of thrombin, the final serine protease in the pathway to generate a fibrin clot, from its precursor is amplified by formation of prothrombinase complex (factor Xa, factor V, Ca.sup.2+ and phospholipid). Since it is calculated that one molecule of factor Xa can generate 138 molecules of thrombin (Elodi, S., Varadi, K.: Optimization of conditions for the catalytic effect of the factor IXa-factor VIII Complex: Probable role of the complex in the amplification of blood coagulation. Thromb. Res. 1979, 15, 617-629), inhibition of factor Xa may be more efficient that inactivation of thrombin in interrupting the blood coagulation system.
Therefore, efficacious and specific inhibitors of factor Xa are needed as potentially valuable therapeutic agents for the treatment of thromboembolic disorders. It is thus desirable to discover new factor Xa inhibitors.